PROJECT 1 NYU Pure autonomic failure (PAF) is a neurodegenerative disorder characterized clinically by orthostatic hypotension (OH) and pathologically by intracellular deposits of the protein alpha synuclein. As in Parkinson disease (PD), in PAF alpha synuclein aggregates in neuronal cytoplasmic inclusions called Lewy bodies (LBs). LB in PAF are numerous in peripheral autonomic neurons with only a few in the substantia nigra and scattered in the CNS. PAF is one of three LB disorders, a category that includes PD and dementia with Lewy bodies (DLB). Each of these disorders affects different neuronal groups relatively selectively, resulting in distinct but overlapping autonomic, motor, and cognitive phenotypes. Because of paucity of data on the natural history of PAF, however, it is not known whether the striatum and other cortical areas remain intact in PAF over time. Specific Aim 1 of this project is to conduct a prospective, longitudinal study to define the natural history of PAF and determine whether the disease remains confined to autonomic neurons or develops eventually into one of the other LB disorders, i.e., PD or DLB. If PAF patients sustain the pure autonomic phenotype, PAF might entail neuroprotective features that prevent the disorder from spreading to the brain affecting motor and cognitive function. Understanding the mechanisms of this neuroprotection could aid in the development of treatments for all LB disorders. The characteristic clinical manifestation of PAF, neurogenic orthostatic hypotension, can also be the initial manifestation of multiple system atrophy (MSA), a neurodegenerative disorder in which alpha synuclein accumulates in glial cytoplasmic inclusions rather than in Lewy bodies. Whereas the three LB disorders involve loss of postganglionic noradrenergic neurons in the heart, these neurons are usually spared in MSA. Therefore, peripheral noradrenergic involvement detected by neurochemical or neuroimaging studies, might be useful as a biomarker of PAF vs. early premotor MSA. In Specific aim 2 we will test the hypothesis that patients who have the clinical phenotype of PAF but have preserved postganglionic sympathetic neurons do not have PAF but have early MSA or other as vet undefined disorders.